The present invention relates to animals that express exogenous growth factors in their milk, and in particular to pigs that express exogenous IGF-I in their milk. The present invention also relates to methods for increasing piglet weight gain and intestinal lactase enzyme activity.
The early neonatal period is the time of greatest animal loss for pork producers. The 1991 USDA National Swine Survey on Morbidity/Mortality and Heath Management of Swine in the U.S. estimated that overall pre-weaning mortality was 15% and that nearly all cases of morbidity and mortality occurred in piglets less than 7 days of age (USDA, 1991). Importantly, 58% of the cases of morbidity were reportedly due to scours and 30% of the mortality was attributed to scours or starvation.
In recent years, pork producers have reduced lactation lengths in an attempt to maximize the number of piglets born per sow per year. Lactation periods of 10-14 days are common in the swine industry. This production system creates a need for sows that produce high levels of milk in early lactation in order to obtain maximal piglet growth. In addition, the number of piglets born per litter has increased, thus adding to the demand for higher milk production early in lactation.
Low milk production is manifested by slow piglet growth before weaning and suboptimal growth post-weaning (Hartman et al., Symp. Zool. Sci., 51:301 [1984]). Milk production accounts for 44% of the growth weight of the piglets (Lewis et al., J. Anim. Sci., 47:634 [1978]). In addition, gastrointestinal disease in piglets reduces their survival. Such diseases are typically treated with antibiotics. It has also been suggested that bioactive substances in milk may have important functions in piglet growth and health.
Clearly, the industry would benefit from a method of increasing milk production and nutrient value in sow milk. Supplementing milk with growth factors or nutrients is too costly and labor-intensive to be a viable solution. The art is in need of a cost effective method of increasing milk production and nutrient value in lactating sows.
The present invention relates to animals that express exogenous growth factors in their milk, and in particular to pigs that express exogenous IGF-I in their milk. The present invention also relates to methods for increasing piglet weight gain and intestinal lactase enzyme activity.
In some embodiments, the present invention provides a transgenic animal having a genome comprising a heterologous nucleic acid sequence encoding a growth factor operably linked to a mammary preferential promoter, wherein descendants of the transgenic animal express an increased amount of growth factor in their milk as compared to control non-transgenic animals. The present invention is not limited to any particular growth factor or source of the nucleic acid encoding the growth factor. Indeed, a variety of growth factors are contemplated, including, but not limited to insulin-like growth factor I, insulin-like growth factor II, epidermal growth factor, platelet derived growth factor, fibroblast growth factor, and transforming growth factor. The present invention is not limited to any particular transgenic animal. Indeed, a variety of transgenic animals are contemplated, including, but not limited to ungulates such as pigs, cattle, sheep, and goats. The animal may be nonhuman. The present invention is not limited to any particular gender of transgenic animal. Indeed, both male and female transgenic animals are contemplated. The present invention is not limited to any particular IGF-I gene. Indeed, a variety of IGF-I genes are contemplated, including, but not limited to human, porcine, and bovine insulin-like growth factor I genes. In some particularly preferred embodiments, the insulin-like growth factor I comprises SEQ ID NO:2. In other preferred embodiments, the heterologous nucleic acid sequence is encoded by SEQ ID NO:1. The present invention is not limited to any particular mammary preferential promoter or source of the nucleic acid encoding the promoter. Indeed, a variety of mammary preferential promoters are contemplated, including, but not limited to alpha-lactalbumin promoters, whey acidic protein promoters, and casein promoters. In some embodiments, the gametes of said transgenic animal comprise said heterologous nucleic acid sequence. When the animal is a heterozygote, it is understood that only a portion of the gametes will comprise the transgene.
In other embodiments, the present invention provides compositions comprising milk from a transgenic animal having a genome comprising a heterologous nucleic acid sequence encoding a growth factor operably linked to a mammary preferential promoter, wherein said milk comprises an increased amount of growth factor as compared to milk from control non-transgenic animals. The present invention is not limited to any particular growth factor or the particular source of the nucleic acid sequence encoding the growth factor. Indeed, a variety of growth factors are contemplated, including, but not limited to insulin-like growth factor I, insulin-like growth factor II, epidermal growth factor, platelet derived growth factor, fibroblast growth factor, and transforming growth factor. The present invention is not limited to any particular transgenic animal. Indeed, a variety of transgenic animals are contemplated, including, but not limited to ungulates such as pigs, cattle, sheep, and goats. The animal may be non-human. The present invention is not limited to any particular gender of transgenic animal. Indeed, both male and female transgenic animals are contemplated. The present invention is not limited to any particular IGF-I gene or the particular source of the nucleic acid encoding the growth factor. Indeed, a variety of IGF-I genes are contemplated, including, but not limited to human, porcine, and bovine insulin-like growth factor I genes. In some particularly preferred embodiments, the insulin-like growth factor I comprises SEQ ID NO:2. In other preferred embodiments, the heterologous nucleic acid sequence is encoded by SEQ ID NO:1. The present invention is not limited to any particular mammary preferential promoter or the particular source of the nucleic acid encoding the promoter. Indeed, a variety of mammary preferential promoters are contemplated, including, but not limited to alpha-lactalbumin promoters, whey acidic protein promoters, and casein promoters.
In still further embodiments, the present invention provides methods for increasing weight gain in a suckling animal, comprising: a) providing i) a transgenic animal having a genome comprising a heterologous nucleic acid sequence encoding a growth factor gene operably linked to a mammary preferential promoter, wherein the transgenic animal expresses an increased amount of growth factor in its milk as compared to control non-transgenic animals; and ii) a suckling offspring of the transgenic animal; and b) providing the suckling offspring milk of said transgenic animal, wherein the suckling offspring has increased weight gain relative to a suckling offspring provided milk of a non-transgenic animal. The present invention is not limited any particular growth factor or the particular source of the nucleic acid encoding the growth factor. Indeed, a variety of growth factors are contemplated, including, but not limited to insulin-like growth factor I, insulin-like growth factor II, epidermal growth factor, platelet-derived growth factor, fibroblast growth factor, and transforming growth factor. The present invention is not limited to any particular transgenic animal. Indeed, a variety of transgenic animals are contemplated, including, but not limited to ungulates such as pigs, cattle, sheep, and goats. The animal may be non-human. The present invention is not limited to any particular gender of transgenic animal. Indeed, both male and female transgenic animals are contemplated. Likewise, in preferred embodiments, the suckling animal can be a piglet, calf, lamb, or kid. The present invention is not limited to any particular IGF-I gene or the particular source of the nucleic acid encoding the growth factor. Indeed, a variety of IGF-I genes are contemplated, including, but not limited to human, porcine, and bovine insulin-like growth factor I genes. In some particularly preferred embodiments, the insulin-like growth factor I comprises SEQ ID NO:2. In other preferred embodiments, the heterologous nucleic acid sequence is encoded by SEQ ID NO:1. The present invention is not limited to any particular mammary preferential promoter or the particular source of the nucleic acid encoding the promoter. Indeed, a variety of mammary preferential promoters are contemplated, including, but not limited to alpha-lactalbumin promoters, whey acidic protein promoters, and casein promoters.
In still other embodiments, the present invention provides methods for increasing intestinal lactase activity in a suckling animal, comprising: a) providing i) a transgenic animal having a genome comprising a heterologous nucleic acid sequence encoding a growth factor operably linked to a mammary preferential promoter, wherein the transgenic animal expresses an increased amount of growth factor in its milk as compared to control non-transgenic animals; and ii) a suckling offspring of the transgenic animal; and b) providing the suckling offspring milk of the transgenic animal, wherein the suckling offspring has increased intestinal lactase activity relative to a suckling offspring provided milk of a non-transgenic animal. The present invention is not limited any particular growth factor or the particular source of the nucleic acid encoding the growth factor. Indeed, a variety of growth factors are contemplated, including, but not limited to insulin-like growth factor I, insulin-like growth factor II, epidermal growth factor, platelet-derived growth factor, fibroblast growth factor, and transforming growth factor. The present invention is not limited to any particular transgenic animal. Indeed, a variety of transgenic animals are contemplated, including, but not limited to ungulates such as pigs, cattle, sheep, and goats. The animal may be non-human. The present invention is not limited to any particular gender of transgenic animal. Indeed, both male and female transgenic animals are contemplated. Likewise, in preferred embodiments, the suckling animal can be a piglet, calf, lamb, or kid. The present invention is not limited to any particular IGF-I gene or the particular source of the nucleic acid encoding the growth factor. Indeed, a variety of IGF-I genes are contemplated, including, but not limited to human, porcine, and bovine insulin-like growth factor I genes. In some particularly preferred embodiments, the insulin-like growth factor I comprises SEQ ID NO:2. In other preferred embodiments, the heterologous nucleic acid sequence is encoded by SEQ ID NO:1. The present invention is not limited to any particular mammary preferential promoter or the particular source of the nucleic acid encoding the promoter. Indeed, a variety of mammary preferential promoters are contemplated, including, but not limited to alpha-lactalbumin promoters, whey acidic protein promoters, and casein promoters.
In some embodiments, the present invention provides methods for increasing intestinal cell division in a suckling animal, comprising: a) providing i) a transgenic animal having a genome comprising a heterologous nucleic acid sequence encoding a growth factor operably linked to a mammary preferential promoter, wherein the transgenic animal expresses an increased amount of growth factor in its milk as compared to control non-transgenic animals; and ii) a suckling offspring of the transgenic animal; and b) providing the suckling offspring milk of the transgenic animal, wherein the suckling offspring has increased intestinal cell division relative to a suckling offspring provided milk of a non-transgenic animal. The present invention is not limited any particular growth factor or the particular source of the nucleic acid encoding the growth factor. Indeed, a variety of growth factors are contemplated, including, but not limited to insulin-like growth factor I, insulin-like growth factor II, epidermal growth factor, platelet derived growth factor, fibroblast growth factor, and transforming growth factor. The present invention is not limited to any particular transgenic animal. Indeed, a variety of transgenic animals are contemplated, including, but not limited to ungulates such as pigs, cattle, sheep, and goats. The animal may be non-human. The present invention is not limited to any particular gender of transgenic animal. Indeed, both male and female transgenic animals are contemplated. Likewise, in preferred embodiments, the suckling animal can be a piglet, calf, lamb, or kid. The present invention is not limited to any particular IGF-I gene. Indeed, a variety of IGF-I genes are contemplated, including, but not limited to human, porcine, and bovine insulin-like growth factor I genes. In some particularly preferred embodiments, the insulin-like growth factor I comprises SEQ ID NO:2. In other preferred embodiments, the heterologous nucleic acid sequence is encoded by SEQ ID NO:1. The present invention is not limited to any particular mammary preferential promoter or the particular source of the nucleic acid encoding the growth factor. Indeed, a variety of mammary preferential promoters are contemplated, including, but not limited to alpha-lactalbumin promoters, whey acidic protein promoters, and casein promoters.
In other embodiments, the present invention provides methods for increasing intestinal villi length in a suckling animal, comprising: a) providing i) a transgenic animal having a genome, said genome comprising a heterologous nucleic acid sequence encoding a growth factor operably linked to a mammary preferential promoter, wherein the transgenic animal expresses an increased amount of growth factor in its milk as compared to control non-transgenic animals; and ii) a suckling offspring of the transgenic animal; and b) providing the suckling offspring milk of said transgenic animal, wherein the suckling offspring has increased intestinal villi length relative to a suckling offspring provided milk of a non-transgenic animal. The present invention is not limited any particular growth factor or the particular source of the nucleic acid encoding the growth factor. Indeed, a variety of growth factors are contemplated, including, but not limited to insulin-like growth factor I, insulin-like growth factor II, epidermal growth factor, platelet derived growth factor, fibroblast growth factor, and transforming growth factor. The present invention is not limited to any particular transgenic animal. Indeed, a variety of transgenic animals are contemplated, including, but not limited to ungulates such as pigs, cattle, sheep, and goats. The animal may be non-human. The present invention is not limited to any particular gender of transgenic animal. Indeed, both male and female transgenic animals are contemplated. Likewise, in preferred embodiments, the suckling animal can be a piglet, calf, lamb, or kid. The present invention is not limited to any particular IGF-I gene. Indeed, a variety of IGF-I genes are contemplated, including, but not limited to human, porcine, and bovine insulin-like growth factor I genes. In some particularly preferred embodiments, the insulin-like growth factor I comprises SEQ ID NO:2. In other preferred embodiments, the heterologous nucleic acid sequence is encoded by SEQ ID NO:1. The present invention is not limited to any particular mammary preferential promoter or the particular source of the nucleic acid encoding the growth factor. Indeed, a variety of mammary preferential promoters are contemplated, including, but not limited to alpha-lactalbumin promoters, whey acidic protein promoters, and casein promoters.
In some embodiments, the present invention provides methods for increasing resistance to intestinal pathogens in a suckling animal, comprising: a) providing i) a transgenic animal having a genome comprising a heterologous nucleic acid sequence encoding a growth factor operably linked to a mammary preferential promoter, wherein the transgenic animal express an increased amount of growth factor in their milk as compared to control non-transgenic animals; ii) a suckling offspring of the transgenic animal; and b) providing the suckling offspring milk of said transgenic animal, wherein the suckling offspring has increased resistance to intestinal parasites relative to a suckling offspring provided milk of a non-transgenic animal. The present invention is not limited any particular growth factor or the particular source of the nucleic acid encoding the growth factor. Indeed, a variety of growth factors are contemplated, including, but not limited to insulin-like growth factor I, insulin-like growth factor II, epidermal growth factor, platelet derived growth factor, fibroblast growth factor, and transforming growth factor. The present invention is not limited to any particular transgenic animal. Indeed, a variety of transgenic animals are contemplated, including, but not limited to ungulates such as pigs, cattle, sheep, and goats. The animal may be non-human. The present invention is not limited to any particular gender of transgenic animal. Indeed, both male and female transgenic animals are contemplated. Likewise, in preferred embodiments, the suckling animal can be a piglet, calf, lamb, or kid. The present invention is not limited to any particular IGF-I gene. Indeed, a variety of IGF-I genes are contemplated, including, but not limited to human, porcine, and bovine insulin-like growth factor I genes. In some particularly preferred embodiments, the insulin-like growth factor I comprises SEQ ID NO:2. In other preferred embodiments, the heterologous nucleic acid sequence is encoded by SEQ ID NO:1. The present invention is not limited to any particular mammary preferential promoter or the particular source of the nucleic acid encoding the promoter. Indeed, a variety of mammary preferential promoters are contemplated, including, but not limited to alpha-lactalbumin promoters, whey acidic protein promoters, and casein promoters. The present invention is not limited to resistance to any particular pathogen. Indeed, resistance to a variety of pathogens is contemplated, including, but not limited to rotovirus, coronavirus, E. coli, and Salmonella.
In some embodiments, the present invention provides a transgenic animal having a genome comprising a nucleic acid sequence encoding a growth factor and encoding alpha-lactalbumin operably linked to a mammary preferential promoter, said animal expressing an increased amount of growth factor and an increased amount of alpha-lactalbumin in its milk as compared to control non-transgenic animals.
In other embodiments, the present invention provides a transgenic animal having a genome comprising a nucleic acid sequence encoding a growth factor and encoding alpha-lactalbumin operably linked to a mammary preferential promoter, said animal expressing an increased amount of growth factor in its milk and an increased milk volume as compared to control non-transgenic animals.
In other embodiments, the present invention provides a method of increasing the volume of milk and the growth factor content of milk in transgenic animals, said method comprising: providing a transgenic animal having a genome, said genome comprising a heterologous nucleic acid sequence encoding a growth factor gene and encoding alpha-lactalbumin operably linked to a mammary preferential promoter, wherein said transgenic animal expresses an increased amount of growth factor in its milk and an increased milk volume as compared to control non-transgenic animals.